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Abstract: FR-OR38

KZR-616, A Selective Inhibitor of the Immunoproteasome: Preclinical and Clinical Mechanism of Action Studies in Lupus Nephritis

Session Information

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation

Authors

  • Muchamuel, Tony, Kezar Life Sciences Inc, South San Francisco, California, United States
  • Fan, Rong Andrea, Kezar Life Sciences Inc, South San Francisco, California, United States
  • Anderl, Janet L., Kezar Life Sciences Inc, South San Francisco, California, United States
  • Johnson, Henry, Kezar Life Sciences Inc, South San Francisco, California, United States
  • Mcminn, Dustin L., Kezar Life Sciences Inc, South San Francisco, California, United States
  • Tuch, Brian, Kezar Life Sciences Inc, South San Francisco, California, United States
  • Kirk, Christopher, Kezar Life Sciences Inc, South San Francisco, California, United States
Background

Selective inhibition of the immunoproteasome blocks progression of nephritis in a mouse model of systemic lupus erythematosus (SLE). Here we describe the effects of KZR-616 in this model and in patients from MISSION (KZR-616-002; NCT03393013), an open-label study of KZR-616 in patients with SLE with and without nephritis.

Methods

24-week old NZB/W mice were treated weekly with subcutaneous administration of 5 mg/kg KZR-616 for 11 weeks. SLE patients with active disease and stable background medication (N=34) were dosed subcutaneously with KZR-616 at 30, 45 or 60 mg weekly for 13 weeks with a 12-week follow-up. Clinical samples were evaluated for proteasome subunit binding, and immune cell profile was evaluated by flow cytometry. Gene expression analysis was performed by RNAseq in mouse tissue (whole blood, spleen, and kidneys) and patient (whole blood) samples.

Results

KZR-616 treatment resulted in complete resolution of proteinuria, prevention of glomeruli damage, and absence of renal IgG deposition. Depletion of splenic activated T- and B-cells and short and long-lived plasma cells in treated animals was noted and correlated with decreased gene expression associated with inflammation, T helper (Th) 1 and Th17 pathways, interferon signaling, antibody secreting cells, and differentiation of plasma cells (PC). KZR-616 reduced kidney tissue transcripts associated with inflammation, cell and myeloid glomerulus trafficking and renal genes implicated in LN pathogenesis. In SLE patients, KZR-616 treatment was determined to be safe and tolerated at all dose levels and reductions in disease activity parameters were noted. KZR-616 treatment was associated with a reduction in class-switched memory B cells and PC in peripheral blood. Decreased expression of gene modules for PC, T-cell activation, inflammation, neutrophil, and type I IFN responses were seen in response to treatment.

Conclusion

KZR-616 resolves nephritis in a mouse model of SLE/LN by regulating immune effector cell gene expression and glomerular injury. In SLE patients, KZR-616 demonstrated broad anti-inflammatory activity across T, B, and innate immune effector cells. These results support further clinical evaluation of KZR-616 in patients with LN.

Funding

  • Commercial Support